Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma
Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma
复制标题
DOI：
10.1172/jci42002
复制
发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Abastado, Jean-Pierre
中科院分区：
文献类型：
--
作者：
Eyles, Jo;Puaux, Anne-Laure;Abastado, Jean-Pierre
虽然转移是癌症相关死亡的主要原因，但尚不清楚为什么一些局部癌症患者在原发肿瘤完全切除后会发生转移性疾病。这种复发归因于肿瘤细胞早期扩散并长时间保持休眠;然而，对这些扩散的肿瘤细胞的控制知之甚少。在这里，我们使用了一个自发的小鼠黑色素瘤模型来研究肿瘤细胞的传播和转移性生长的免疫控制。发现肿瘤细胞在原发性肿瘤的早期发展中遍布全身，甚至在临床上可检测到之前。播散的肿瘤细胞根据组织保持不同的休眠期，导致交错的转移性生长。相对于原发性肿瘤，肺中的休眠与播散性肿瘤细胞的增殖减少有关。这至少部分是由抑制细胞生长的CD 8（+）T细胞介导的，因为这些细胞的耗竭导致内脏转移瘤生长更快。我们的研究结果预测，免疫反应有利于休眠的播散性肿瘤细胞，我们建议是随后的宏观转移的种子，是必不可少的延长早期癌症患者的生存期，并建议治疗策略，旨在加强这种免疫反应可能会产生显着的好处，在这些患者。
Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8(+) T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients.